Metformin sensitizes insulin signaling through AMPK-mediated pten down-regulation in preadipocyte 3T3-L1 cells

Soo Kyung Lee, Jung Ok Lee, Ji Hae Kim, Su Jin Kim, Ga Young You, Ji Wook Moon, Jin Hee Jung, Sun Hwa Park, Kyung Ok Uhm, Ji Man Park, Pann Ghill Suh, Hyeon Soo Kim

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Insulin resistance is the primary cause responsible for type 2 diabetes. Phosphatase and tensin homolog (PTEN) plays a negative role in insulin signaling and its inhibition improves insulin sensitivity. Metformin is a widely used insulin-sensitizing drug; however, the mechanism by which metformin acts is poorly understood. To gain insight into the role of PTEN, we examined the effect of metformin on PTEN expression. Metformin suppressed the expression of PTEN in an AMP-activated protein kinase (AMPK)-dependent manner in preadipocyte 3T3-L1 cells. Knock-down of PTEN potentiated the increase in insulin-mediated phosphorylation of Akt/ERK. Metformin also increased the phosphorylation of c-Jun N-terminal kinase (JNK)-c-Jun and mammalian target of rapamycin (mTOR)-p70S6 kinase pathways. Both pharmacologic inhibition and knock-down of AMPK blocked metformin-induced phosphorylation of JNK and mTOR. Knock-down of AMPK recovered the metformin-induced PTEN down-regulation, suggesting the involvement of AMPK in PTEN regulation. PTEN promoter activity was suppressed by metformin and inhibition of mTOR and JNK by pharmacologic inhibitors blocked metformin-induced PTEN promoter activity suppression. These findings provide evidence for a novel role of AMPK on PTEN expression and thus suggest a possible mechanism by which metformin may contribute to its beneficial effects on insulin signaling.

Original languageEnglish
Pages (from-to)1259-1267
Number of pages9
JournalJournal of cellular biochemistry
Volume112
Issue number5
DOIs
Publication statusPublished - 2011 May

Keywords

  • AMPK
  • PTEN
  • adipocyte
  • insulin
  • metformin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Lee, S. K., Lee, J. O., Kim, J. H., Kim, S. J., You, G. Y., Moon, J. W., Jung, J. H., Park, S. H., Uhm, K. O., Park, J. M., Suh, P. G., & Kim, H. S. (2011). Metformin sensitizes insulin signaling through AMPK-mediated pten down-regulation in preadipocyte 3T3-L1 cells. Journal of cellular biochemistry, 112(5), 1259-1267. https://doi.org/10.1002/jcb.23000